DILTIAZEM

Fetal Risk Summary

Diltiazem is a calcium channel inhibitor used for the treatment of angina. Reproductive studies in mice, rats, and rabbits at doses up to 5–10 times (on a mg/kg basis) the daily recommended human dose found increased mortality in embryos and fetuses (1). These doses also produced teratogenic effects involving the skeletal system (1). An increased incidence of stillbirths was observed in perinatal animal studies at 20 times the human dose or greater (1). In fetal sheep, diltiazem, like ritodrine and magnesium sulfate, inhibited bladder contractions, resulting in residual urine (2).

A 34-year-old woman, in her 1st month of pregnancy, was treated with diltiazem, 60 mg 4 times/day, and isosorbide dinitrate, 20 mg 4 times/day, for symptomatic myocardial ischemia (3). Both medications were continued throughout the remainder of gestation. Normal twins were delivered by repeat cesarean section at 37 weeks' gestation. Both infants were alive and well at 6 months of age.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 27 newborns had been exposed to diltiazem during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Four (14.8%) major birth defects were observed (one expected), two of which were cardiovascular defects (0.3 expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which data were available. Although the number of exposures is small, the total number of defects and the number of cardiovascular defects are suggestive of an association, but other factors, including the mother's disease, concurrent drug use, and chance may be involved.

A prospective, multicenter cohort study of 78 women (81 outcomes; 3 sets of twins) who had 1st trimester exposure to calcium channel blockers, including 13% to diltiazem, was reported in 1996 (4). Compared to controls, no increase in the risk of major congenital malformations was found.

Diltiazem has been used as a tocolytic agent (5). In a prospective randomized trial, 22 women treated with the agent were compared with 23 treated with nifedipine. No differences between the groups in outcomes or maternal effects were observed.

Breast Feeding Summary

Diltiazem is excreted into human milk (6). A 40-year-old woman, 14 days postpartum, was unsuccessfully treated with diltiazem, 60 mg 4 times/day, for resistant premature ventricular contractions. Her infant was not allowed to breast-feed during the treatment period. Simultaneous serum and milk levels were drawn at several times on the 4th day of therapy. The peak level in milk was approximately 200 ng/mL, almost the same as the peak serum concentration. Milk and serum concentrations were nearly the same during the measurement interval, with changes in the concentrations closely paralleling each other. The data indicated that diltiazem freely diffuses into milk (6). In a separate case described above, a mother nursed twins for at least 6 months while being treated with diltiazem and isosorbide dinitrate (3). Milk concentrations were not determined, but both infants were alive and well at 6 months of age. The American Academy of Pediatrics considers the use of diltiazem to be compatible with breast feeding (7).

References

1. Product information. Cardizem. Hoechst Marion Roussel, 1997.
2. Kogan BA, Iwamoto HS. Lower urinary tract function in the sheep fetus: studies of autonomic control and pharmacologic responses of the fetal bladder. J Urol 1989;141:1019–24.
3. Lubbe WF. Use of diltiazem during pregnancy. NZ Med J 1987;100:121.
4. Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B, Cook L, McElhatton PR, Schmidt MA, Koren G. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol 1996;174:823–8.
5. El-Sayed Y, Holbrook RH Jr. Diltiazem (D) for the maintenance tocolysis of preterm labor (PTL): a prospective randomized trial (abstract). Am J Obstet Gynecol 1996;174:468.
6. Okada M, Inoue H, Nakamura Y, Kishimoto M, Suzuki T. Excretion of diltiazem in human milk. N Engl J Med 1985;313:992–3.
7. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.